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J L Ware

Publications and source records attributed to J L Ware.

At least 37 records · Page 2Linked to original sources
PubMed1994

p53 tumor suppressor oncogene expression in squamous cell carcinoma of the hypopharynx.

BACKGROUND: Although abnormalities of the p53 tumor suppressor oncogene system are being detected in many human cancers, the frequency and prognostic significance of such events in squamous cell cancer of the head and neck remain unknown. METHODS: Immunohistochemical studies were performed on archival tumor tissue taken from 43 patients with squamous cell carcinoma of the hypopharynx. Statistical analyses examining potential associations between p53 oncoprotein accumulation and various clinicopathologic parameters (including survival) were conducted. RESULTS: Sixteen (37%) tumors demonstrated strong specific staining for p53. Patients whose tumors stained strongly for p53 were significantly younger, presented at a more advanced clinical disease stage, and tended to have increased expression of epidermal growth factor receptor (P = 0.056). There was no correlation between p53 expression and the incidence of multiple primary cancers, tumor grade, DNA ploidy, or percent of S-phase. Median survival times were 11.6 months and 18.0 months for the p53-positive and p53-negative groups (NS). A Cox regression analysis confirmed the lack of significance of p53 in overall survival. CONCLUSIONS: These data suggest that although abnormalities of the p53 oncoprotein are common in this cancer, this finding is of little clinical significance.

Age Factors↗
PubMed1994

Insulin-like growth factor-binding protein-3 expression and secretion by cultures of human prostate epithelial cells and stromal fibroblasts.

Prostate-specific antigen (PSA) was recently shown to be an insulin-like growth factor-binding protein (IGFBP)-3 protease. However, only IGFBPs-2 and -4 have been identified in conditioned medium of prostate epithelial cells. Using cultures of human prostate epithelial and stromal fibroblastic cells, we examined conditioned medium and cell extracts for evidence of IGFBP-3 expression and secretion. Western ligand blotting of conditioned medium from epithelial or stromal cultures revealed the presence of IGFBPs in the molecular weight range 36-48 kDa, suggestive of IGFBP-3. Western immunoblots of these media confirmed the presence of IGFBP-3. Northern analyses of extracts of both stromal and epithelial cells showed a 2.5 kb band, the size of IGFBP-3 mRNA. We conclude that prostate cells express IGFBP-3 and that local proteolysis by PSA could modify this binding protein's actions in the prostate.

Blotting, Northern↗
PubMed1994

Evaluation of cathepsin D and epidermal growth factor receptor in prostate carcinoma.

Differential reactivity for cathepsin D (cath-D) and epidermal growth factor receptor (EGFR) was compared in 102 archival cases of human primary prostatic carcinoma and nine prostate carcinoma metastases by immunohistochemical techniques using commercially available antibodies (Ciba-Corning, Triton Diagnostics Division, Alameda, CA). Western immunoblotting confirmed that the anti-cath-D and anti-EGFR antibodies recognized the appropriate-sized proteins in extracts of human prostatic carcinoma cell lines. For immunohistochemical analysis, the primary prostate carcinomas ranged from Gleason's combined scores of 2 to 9. High-grade prostatic intraepithelial neoplasia was coexistent in 79 of the cases. Immunohistochemical staining was scored by summing the intensity of staining (0 to 3+) weighted by the percentage of tumor staining at each intensity (H score, theoretical range 0 to 300). Heterogenous moderate to strong reactivity with anti-cath-D was detected in 96 of 102 cases of primary prostate carcinoma (94%), with a mean H score of 176.5. EGFR reactivity was much less common and less strong, with 41 of 102 primary prostate carcinomas staining (40%) at a mean H score intensity of 29.2. The immunohistochemical (H) scores of cath-D and EGFR reactivity both significantly correlated with the Gleason's combined score of the tumors. There was no significant correlation between the cath-D and EGFR scores. Ninety-nine percent of the examples of prostatic intraepithelial neoplasia were reactive with anti-cath-D, with no clear correlation between the intensity of staining of prostatic intraepithelial neoplasia and the adjacent carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1994

Prostate cancer progression. Implications of histopathology.

This review examines selected areas of contemporary prostate cancer research in terms of the impact of prostatic cellular and histopathological heterogeneity. Prostate tumor progression is accompanied by dysregulation of multiple growth factor networks as well as disruption of normal patterns of cell-cell interactions. Molecular and cytogenetic studies demonstrate that prostate cancer results from the accumulation of several different genetic defects. No single event predominates, but modifications in tumor suppressor genes or functional elimination of the suppressor gene product are more common than activation of known oncogenes. Intratumor heterogeneity is also detectable at the genetic level. This further complicates efforts to correlate modifications at specific loci with progression or outcome. The development of new in vitro and in vivo systems for the study of human prostate cancer should increase our understanding of this complex disease. In each approach, knowledge of the histopathology of the normal and neoplastic prostate is essential.

Animals↗
PubMed1993

Documented need for more effective diagnosis and treatment of familial hypercholesterolemia according to data from 502 heterozygotes in Utah.

A project to help Utah residents with heterozygous familial hypercholesterolemia (FH) identified affected individuals by collecting detailed questionnaires from: (1) very high-risk persons in computer files of screening data (very high cholesterol levels, very early coronary artery disease, and strong positive family history); (2) confirmed FH index cases from a university lipid clinic; and (3) relatives of any confirmed FH cases. Questionnaires were received from 2,143 persons identifying 101 living index cases and 502 relatives meeting the criteria for the diagnosis of FH. Finding new FH heterozygotes was about one fourth as expensive by tracing relatives of confirmed FH cases by evaluating very high-risk persons. Of those meeting criteria for the diagnosis of heterozygous FH, only 31% reported being told by their physicians that they had FH, only 42% indicated that they were taking a cholesterol-lowering prescription medication, and only 23% had reasonably controlled cholesterol levels (below the 90th percentile). However, the data also suggest that good control is achievable in motivated patients. Among 106 FH heterozygotes who were early responders to a second follow-up questionnaire, 79% were taking prescription medications, of whom 49% had achieved cholesterol levels below the 90th percentile, and 17% even achieved cholesterol levels below the 50th percentile. We conclude that most patients with heterozygous FH are not diagnosed and not adequately treated. We demonstrated how many of these persons needing help could be identified efficiently by tracing relatives of known index cases.

Adolescent↗
PubMed1993

Growth factors and their receptors as determinants in the proliferation and metastasis of human prostate cancer.

Prostate adenocarcinoma, the most common tumor occurring among North American men, preferentially metastasizes to bone, where it characteristically forms osteoblastic lesions. The following growth regulatory factors are expressed in some human prostate cancers and/or established cell lines: epidermal growth factor (EGF), transforming growth factor alpha, transforming growth factor beta, basic fibroblast growth factor (bFGF), and insulin-like growth factor. Some of these, especially EGF, bFGF, and TGF-beta, are also implicated in growth regulation in normal and benign hyperplastic prostates. Although evidence from in vitro study of the small number of prostate cell lines available demonstrates that these growth regulatory pathways are exploited by some of these cells, direct in vivo evidence is limited. The development of human prostate cancer cell lines which grow and metastasize in immune-deficient rodents is an advance which now permits experimental analysis of the role of these growth factors in prostatic metastasis, particularly to bone. The progression and metastasis of human prostate cancer results from the complex interactions of multiple growth factors, androgens, and cellular communication, which form a dynamic network. Continued progress in the study and treatment of this disease will require new conceptual frameworks as well as successful application of the techniques of molecular and cellular biology.

Animals↗
PubMed1993

Epidermal growth factor receptor expression in squamous cell carcinoma of the hypopharynx.

Expression of the epidermal growth factor receptor (EGFR) has been demonstrated in normal and malignant squamous epithelia. Its presence has been suggested to be important in the pathophysiology and prognosis of epithelial cancers. Archival tumour specimens from 57 patients with squamous cell carcinoma of the hypopharynx were studied using OM-11-951, a new murine anti-EGFR monoclonal antibody which recognizes the receptor on deparaffinized tissue. By visual inspection, 28 (49%) tumours were EGFR negative; 29 (51%) tumours were EGFR positive. While patients whose tumours were EGFR positive were younger, there was no significant correlation with other clinical or pathological variables (including grade and stage). Patients whose tumours were EGFR negative had a median survival of 21 (95% CI 4.3-37.7) months compared with a median survival of 17 (95% CI 11.4-22) months for patients whose tumours were EGFR positive. The difference was not statistically significant. A multiple regression analysis did not demonstrate EGFR status to be important in predicting survival. These data cast doubt on the prognostic significance of EGFR expression in this neoplasm.

Antibodies, Monoclonal↗
PubMed1993

A modified neural network model of tumor cell interactions and subpopulation dynamics.

Tumors consist of phenotypically heterogeneous subpopulations of cells which are frequently affected by both autocrine and paracrine factors. Applying concepts from neural network theory, we have developed a computer model of chemical communication among hypothetical tumor cells, which simulates some of the complex epigenetic behavior of real tumors. Deletion of subpopulations often destabilized the whole population. The impact of deletion of specific subpopulations was affected by (a) which subpopulation was deleted, and (b) the timing of the deletion during tumor progression.

Cell Communication↗
PubMed1992

Isolation and characterization of transforming growth factor beta response variants from human prostatic tumor cell lines.

In this study we examined the relation between the response to transforming growth factor beta (TGF beta 1) in vitro and the growth in vivo of 1-LN-PC3-1A (1-LN) human prostatic carcinoma cells. 1-LN cells resistant to the growth-inhibitory effects of TGF beta 1 were isolated after exposure to 2 ng/ml TGF beta 1 in an anchorage-independent growth assay. Cloning of TGF beta 1-resistant and -sensitive populations produced 2 clones (R2-6 and 1-LN clone 4), which maintained relatively stable resistance or sensitivity, respectively, in the absence of TGF beta 1 for up to 12 passages. Colony formation by the R2-6 cells in the presence of TGF beta 1 was 2-10 times greater than that of 1-LN clone 4, depending upon the TGF beta 1 concentration. Injection of 1 x 10(5) R2-6 cells into athymic nude mice produced tumors with a significantly shorter latency interval as compared with 1-LN clone 4 tumors (P < 0.0001). Western immunoblotting showed that higher levels of latent TGF beta 1 protein were secreted into the culture medium by 1-LN clone 4 cells. Acidified conditioned media from both clones inhibited mink lung epithelial cell DNA synthesis. Neutralizing monoclonal antibody to TGF beta 1 but not TGF beta 2 abrogated this inhibitory effect. Comparison of the different sensitive and resistant clones showed that in vitro sensitivity to TGF beta 1 and in vivo tumor latency interval were not invariably correlated. Thus, the TGF beta 1 response phenotype in vitro was not always predictive of growth delay in vivo.

Animals↗
PubMed1992

Localization of epidermal growth factor receptor by immunohistochemical methods in human prostatic carcinoma, prostatic intraepithelial neoplasia, and benign hyperplasia.

The epidermal growth factor receptor (EGFr) is a membrane-bound glycoprotein that is present in a wide variety of human normal and malignant tissues. In this study EGFr expression in frozen sections of prostate tissue obtained from 40 different surgical specimens was examined immunohistochemically with a well-characterized monoclonal antibody to EGFr, Ab-1 (Oncogene Science). Twenty cases of prostate adenocarcinoma and 20 cases of benign prostatic hyperplasia were studied. Six of the 20 cases of adenocarcinoma also contained prostatic intraepithelial neoplasia grade III (severe intraductal dysplasia). All of the cases containing benign glands showed strong immunostaining in a continuous or nearly continuous pattern, with staining restricted to the basal layer of the benign glands. Adenocarcinoma lacked immunostaining in 15 (75%) of 20 cases, while the remaining five cases (25%) showed diffuse cytoplasmic staining, which was weaker than that seen in the benign glands and that lacked basal accentuation. The six cases that contained prostatic intraepithelial neoplasia grade III showed a discontinuous basal pattern of staining, and the gaps in the staining appeared to correspond to areas of disruption of the basal cell layer. We conclude that the antigenic determinant recognized by this antibody to EGFr was detected preferentially in the basal layer in benign prostatic glands. In contrast, a minority of cases of adenocarcinoma expressed EGFr, as assessed by immunoreactivity with the Ab-1 monoclonal antibody. Prostatic intraepithelial neoplasia grade III expressed EGFr with a predominantly discontinuous basal pattern that corresponded to the disrupted basal cell layer typical of this process.

Adenocarcinoma↗
PubMed1991

Immunohistochemical detection of c-erbB-2 protein in human benign and neoplastic prostate.

Both the polyclonal anti-c-erbB-2 peptide antiserum pAB 60 and the monoclonal anti-c-erbB-2 protein antibody mAB-1 detect the c-erbB-2 protein in human breast adenocarcinomas. We investigated c-erbB-2 expression in adult human benign hyperplastic and neoplastic prostates, using the avidin-biotin complex immunoperoxidase method. Formalin-fixed, paraffin-embedded specimens of benign hyperplastic prostate (13), prostatic adenocarcinoma (22), and prostatic adenocarcinoma lymph node metastases (two) were tested with pAB 60. Ten formalin-fixed, paraffin-embedded specimens of prostate adenocarcinoma, 11 frozen sections of benign hyperplastic specimens, and eight frozen sections of prostate adenocarcinoma were tested with mAB-1. Our results demonstrated consistent detection of c-erbB-2 immunohistochemically in frozen sections of both benign and malignant prostate. Preincubation of pAB 60 with the immunizing peptide blocked subsequent reactivity with prostatic tumor tissue, indicating specificity. However, fixation and processing protocols significantly affected the reactivity of the antigenic determinants detected by these antibodies, as mAB-1 was nonreactive with formalin-fixed, paraffin-embedded prostatic tissues. Differential reactivity of pAB 60 with malignant rather than benign glands was maximized by exposure of the specimen to the antibody at 4 degrees C rather than 22 degrees C. The most frequently observed staining pattern with both antibodies was cytoplasmic. However, mAB-1 produced distinctly membranous staining in two frozen specimens of benign hyperplasia and one specimen of prostate cancer.

Adenocarcinoma↗
PubMed1991

Effect of radiation combined with hyperthermia on human prostatic carcinoma cell lines in culture.

The effect of radiation combined with heat on three human prostatic carcinoma cell lines growing in vitro was investigated. Cells were exposed to different radiation doses followed by heat treatment at 43 degrees C for one hour. Heat treatment, given ten minutes after radiation, significantly enhanced the radiation response of all the cell lines studied. The combined effect of radiation and heat produced greater cytotoxicity than predicted from the additive effects of the two individual treatment modalities alone. These results indicate that a combined treatment regimen of radiation plus hyperthermia (43 degrees, 1 hr) might be an important tool in maintaining a better local control of prostatic cancer.

Cell Survival↗
PubMed1991

The effect of radiation therapy and hyperthermia on a human prostatic carcinoma cell line grown in athymic nude mice.

The effect of radiation and/or hyperthermia on a human prostatic carcinoma xenograft in athymic nude mice was investigated. A human prostate carcinoma subline (1-LN-PC-3-1A) was inoculated subcutaneously in the thigh of male athymic nude mice. When tumors reached a size of approximately 200 mm.3, they were treated with either radiation (X) or hyperthermia (H) alone, or in combination (X + H). In the combined treatment, hyperthermia was delivered immediately after radiation exposure. Comparison of the time required to reach twice the tumor volume observed at the time of treatment was used to define therapeutic impact on tumor growth. The combined treatment resulted in median tumor volume doubling time of 35.5 days, compared to 18 days and 25.5 days, respectively, for hyperthermia or radiation alone. Analysis of tumor doubling time using a proportional hazards regression indicates that under the conditions of this experiment, the effect of radiation and hyperthermia for 1-LN-PC-3-1A tumors is additive. The impact of this treatment regimen in the management of prostatic cancer requires further investigation.

Animals↗
PubMed1989

The effect of hyperthermia on human prostatic carcinoma cell lines: evaluation in vitro.

The effect of hyperthermia on established human prostate carcinoma cell lines (PC-3, DU-145) and related sublines (1-LN, 125-1L) was investigated in vitro. Cells were exposed to heat treatment at 43C or 37C for varying time intervals, (one hr or two hrs) and cell survival was evaluated by the colony formation assay and by measurement of cellular growth rate. While one hr exposure at 43C did show a mean inhibition of colony formation, ranging from 29 to 41%, a statistically significant increase in inhibition rate (p less than 0.001) was observed at two hr exposure, ranging from 57 to 92%. This study is a report of the cytotoxic effect of hyperthermia on established human prostatic tumor cell lines. These in vitro results indicate that hyperthermia may become a potentially useful form of adjunctive therapy for local control of prostatic cancer. However, the temperature and exposure time may have an important impact on cell kill when this new modality for cancer treatment is proposed for a clinical trial.

Cell Line↗
PubMed1989

Molecular cloning of a cDNA encoding canine factor IX.

Factor IX (F.IX) is a vitamin K-dependent plasma protein, a deficiency of which results in hemophilia B. A canine model of hemophilia B exists; attempts to use this model for gene transfer experiments or characterization of the hemophilic defect require elucidation of normal canine F.IX structure. We report the isolation and characterization of the coding region for canine F.IX cDNA. Canine F.IX possesses 86% identity at the amino-acid level with human F.IX. The leader peptide, Gla domain, EGF domains, and the carboxy-terminal portion of the heavy chains show extensive sequence conservation between the canine and human. All Glu residues undergoing gamma-carboxylation in humans are conserved in canines. The complete coding sequence for canine F.IX has been determined, and the derived translation product has been analyzed. A similar approach should allow identification of the causative mutation in canine hemophilia B. Furthermore, this clone may prove a valuable resource in gene transfer experiments for this disease.

Amino Acid Sequence↗
PubMed1988

Clonal variation in the impact of ethyl methanesulfonate and 5-azacytidine on the metastatic phenotype of human prostatic tumor cells in athymic nude mice.

Parallel in vitro exposure to 5-azacytidine or to ethyl methanesulfonate either significantly reduced or had no major impact on the experimental metastasis capacity of different clones of the human prostatic carcinoma subline 1-LN-PC-3-1A. The impact of these agents on metastatic capacity varied (1) among different clones and (2) between clones and the uncloned parental line. Analysis of the process by which these agents modify the metastatic phenotype of human tumor cells may offer insight into the process of phenotypic diversification.

Animals↗